Diphenols, particularly those derived from tyrosine, are monomeric starting materials for biocompatible polycarbonates, polyiminocarbonates, polyarylates, polyurethanes, and the like. U.S. Pat. Nos. 5,099,060, 5,198,507, and 5,670,602 disclose amino acid-derived diphenol compounds useful in the preparation of polyarylates, polycarbonates and polyiminocarbonates. The polymers, for example those described in U.S. Pat. Nos. 4,980,449, 5,216,115, 5,658,995, 6,048,521, and 6,120,491, and U.S. patent application publication No. 2004/0254334, are useful as degradable polymers in general, and are particularly useful as tissue-compatible bioerodible materials for medical uses. The suitability of these polymers for this end use application is at least in part the result of their derivation from diphenols derived from the naturally-occurring amino acid L-tyrosine.
The polycarbonates in particular are strong, water-insoluble materials most suitable for use as structural implants. The L-tyrosine derived polyarylates described in U.S. Pat. No. 5,216,115, and the poly(alkylene oxide) block copolymers with these polyarylates disclosed in U.S. Pat. No. 5,658,995, feature protected carboxylic acid groups, and these polymers are limited in application because of their slow rate of degradation and significant hydrophobicity. The free acid forms of the polymers, described in U.S. Pat. No. 6,120,491 (“the '491 patent”), in which to varying degrees the ester protecting groups have been removed from the pendent carboxylic acid chains of the diphenols, are less hydrophobic and exhibit an increased degradation rate (i.e. backbone cleavage) compared to their counterparts with fully esterified carboxylic acid groups. Increasing the amount of pendant carboxylic acid diphenol contained within a particular polymer increases the hydrophilicity (water uptake) of the polymer; however, its relative complete resorption rate does not change significantly. This is because the mechanism of degradation—namely, backbone cleavage to successively smaller units containing diphenols with ester protected carboxylic acid groups—does not change the relative water solubility of the esterified monomeric units incorporated within the polymer chains, nor, in the case of the tyrosine-derived polyarylates, does it change the relative water solubility of the diacids with which they are condensed. Therefore, the introduction of an increasing fraction of free carboxylic acid side chains only increases the hydrophilicity of the polymer itself. It does not significantly impact the resorption rate of the ester diphenol fragments produced by polymer backbone degradation.
Hence, medical devices comprised of such materials will retain some significant portion of their mass for roughly the same time period as those polymers described in U.S. Pat. No. 5,099,060, which describes polymers with diphenol monomeric units that lack carboxylic acid side chains. Such polymers resorb completely only in time periods in excess of 1 year, and in many cases in closer to 2-2.5 years. The diphenol monomeric units of these polymers are significantly hydrophobic and have low water solubility.
The '491 patent describes polymers formed from a similar series of diphenol monomeric units but which contain repeating units of the same general diphenol monomers with both protected and unprotected carboxylic acid side chains. The '491 patent teaches that “the incorporation of pendent carboxylic acid groups within the polymer bulk has a dramatic and previously unrecognized accelerating effect on the rate of polymer backbone degradation and resorption both in vitro and in vivo.” However, the present inventors have surprisingly found that incorporating some fraction of diphenol monomers with pendant carboxylic acid groups into the polymer does not accelerate overall resorption, because the monomers with protected carboxylic acid groups remain too hydrophobic for resorption on desirable time scales. For example, a polymer incorporating 10% pendant carboxylic acid side chain will degrade (by backbone cleavage) at a faster rate than one containing no pendant carboxylic acid side chains, and some resorption will occur, but this resorption is due to the water solubility of the diphenol monomers containing the pendant carboxylic acid groups. Once this monomer is resorbed, the remaining polymer, albeit one of smaller chain length, contains the protected carboxylic acid side chain monomers which are hydrophobic and resorb at a very slow rate. Incorporating a high fraction of pendant carboxylic acid side chain monomer (e.g., 50% of the diphenol monomer content of the polymer) essentially creates a water-soluble polymer that solubilizes and undergoes degradation until the polymer chain fragments that are enriched in protected pendant carboxylic acid groups precipitate out of solution. The preferred protected monomers in the '491 patent are actually the most hydrophobic and therefore the slowest to resorb, i.e. the ethyl, butyl, hexyl, and octyl esters.
Complete, or nearly complete, polymer resorption (e.g., at least 90%, 95%, 96%. 97%. 98%, 99%, 99.5%, or 100%) is important in the use of “biodegradable” polymers in medical devices. Biodegradable and resorbable polymers are primarily used to deliver drugs for a finite period of time or to serve some other temporary purpose, such as to provide a biocompatible surface, enhanced tissue growth, or extra strength during implantation. Polymers that do not completely resorb leave remnants that can cause anything from minor inflammation and pain to excess scarring, and in the case of cardiovascular implants, such remnants can cause thrombosis and possibly patient death.